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Peer-reviewedCC BY 4.0PLOS Pathogens

Elevated Plasmodium falciparum sexual conversion in HbAC and HbAS red blood cells in naturally infected malaria patients

  • Yasmina Drissi-El Boukili1
  • Vera Kühne2
  • H. Magloire Natama3
  • Pieter Moris4
  • Elisabet Tintó-Font5
  • Antonia Windkouni Bere6
  • Odin Goovaerts7
  • Pieter Guetens8
  • Ana Moreno-Murillo
  • Yarno Valgaerts
  • T. Edwig Traoré
  • D. Florence Ouedraogo
5 more authors
  • Halidou Tinto
  • Ann Van de Velde
  • Alfred Cortés
  • Guy Caljon
  • Anna Rosanas-Urgell
8 affiliations
  1. 1Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
  2. 2Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium
  3. 3Unité de Recherche Clinique de Nanoro, Institut de Recherche en Sciences de la Santé, Nanoro, Burkina Faso
  4. 4ISGlobal, Barcelona, Catalonia, Spain
  5. 5Laboratoire de Biochimie et d’Immunologie Appliquées (LaBIA), Ecole Doctorale Sciences et Technologies, Université Joseph Ki-Zerbo, Ouagadougou, Burkina Faso
  6. 6Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
  7. 7Hematology and Hemostasis Unit, Universitair Ziekenhuis Antwerpen (UZA), Antwerp, Belgium
  8. 8ICREA, Barcelona, Catalonia, Spain
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Abstract

Malaria transmission relies on the differentiation of asexual parasites into gametocytes, a process initiated by sexual conversion (SC). Mutations in the host hemoglobin beta (HBB) gene are known to influence parasite growth and disease outcome, yet their impact on SC remains unclear. We investigated the effect of HBB mutant genotypes on Plasmodium falciparum (P. falciparum) SC and humoral immunity in individuals from Nanoro, Burkina Faso. To measure SC rates in natural human malaria infections, we developed a new ex vivo SC assay (evSCA). We found that in human natural P. falciparum infections, SC rates were higher in individuals with HbAS or HbAC than in individuals with wild-type HBB (HbAA). Consistently, using an in vitro SC assay (ivSCA) based on the NF54-gexp02-Tom reporter line we found that cultures grown in HbAS red blood cells (RBCs) had higher SC rates than those grown in HbAA RBCs. Furthermore, IgG and IgM responses against trophozoite- and stage I gametocyte-infected RBC antigens, quantified by flow cytometry, did not differ between plasma from individuals with different HBB genotypes. These results demonstrate that exposure to RBCs with HBB mutations enhances SC, highlighting a host-genetic factor that may influence malaria transmission potential. Author summary: Transmission of Plasmodium falciparum, a malaria causing parasite, depends on the parasite’s ability to produce gametocytes, the stage that infects mosquitoes. In many African regions where malaria is common, hemoglobin (Hb) variants such as hemoglobin S (the sickle-cell trait) and C are highly prevalent reflecting their role in protecting against severe disease. However, it remains unclear whether these variants also influence the parasite’s early shift toward gametocyte development (i.e., sexual conversion [SC]). In this study, we combined ex vivo and in vitro SC assays to measure SC in red blood cells with different hemoglobin genotypes. We found that SC was higher in parasites growing in red blood cells carrying hemoglobin AC and AS genotypes compared to normal AA hemoglobin. These findings provide experimental support for earlier epidemiological observations reporting that individuals with these hemoglobin variants often carry more gametocytes and are more infectious to mosquitoes. We also measured antibody levels in individuals with mutant RBCs and found no differences in immunity that could explain the variation in SC. Our results show that host genetic background can influence gametocyte development and may shape the infectious reservoir in high-burden settings. This knowledge is important for designing effective strategies for malaria elimination.

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Cite

BibTeXRIS
BibTeX
@article{boukili2026elevated,
  title = {{Elevated Plasmodium falciparum sexual conversion in HbAC and HbAS red blood cells in naturally infected malaria patients}},
  author = {Yasmina Drissi-El Boukili and Vera Kühne and H. Magloire Natama and Pieter Moris and Elisabet Tintó-Font and Antonia Windkouni Bere and Odin Goovaerts and Pieter Guetens and Ana Moreno-Murillo and Yarno Valgaerts and T. Edwig Traoré and D. Florence Ouedraogo and Halidou Tinto and Ann Van de Velde and Alfred Cortés and Guy Caljon and Anna Rosanas-Urgell},
  journal = {PLOS Pathogens},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.ppat.1014542},
  url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014542},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Elevated Plasmodium falciparum sexual conversion in HbAC and HbAS red blood cells in naturally infected malaria patients
AU  - Yasmina Drissi-El Boukili
AU  - Vera Kühne
AU  - H. Magloire Natama
AU  - Pieter Moris
AU  - Elisabet Tintó-Font
AU  - Antonia Windkouni Bere
AU  - Odin Goovaerts
AU  - Pieter Guetens
AU  - Ana Moreno-Murillo
AU  - Yarno Valgaerts
AU  - T. Edwig Traoré
AU  - D. Florence Ouedraogo
AU  - Halidou Tinto
AU  - Ann Van de Velde
AU  - Alfred Cortés
AU  - Guy Caljon
AU  - Anna Rosanas-Urgell
PY  - 2026
DA  - 2026/09/29
JO  - PLOS Pathogens
DO  - 10.1371/journal.ppat.1014542
UR  - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014542
AB  - Malaria transmission relies on the differentiation of asexual parasites into gametocytes, a process initiated by sexual conversion (SC). Mutations in the host hemoglobin beta (HBB) gene are known to influence parasite growth and disease outcome, yet their impact on SC remains unclear. We investigated the effect of HBB mutant genotypes on Plasmodium falciparum (P. falciparum) SC and humoral immunity in individuals from Nanoro, Burkina Faso. To measure SC rates in natural human malaria infections, we developed a new ex vivo SC assay (evSCA). We found that in human natural P. falciparum infections, SC rates were higher in individuals with HbAS or HbAC than in individuals with wild-type HBB (HbAA). Consistently, using an in vitro SC assay (ivSCA) based on the NF54-gexp02-Tom reporter line we found that cultures grown in HbAS red blood cells (RBCs) had higher SC rates than those grown in HbAA RBCs. Furthermore, IgG and IgM responses against trophozoite- and stage I gametocyte-infected RBC antigens, quantified by flow cytometry, did not differ between plasma from individuals with different HBB genotypes. These results demonstrate that exposure to RBCs with HBB mutations enhances SC, highlighting a host-genetic factor that may influence malaria transmission potential. Author summary: Transmission of Plasmodium falciparum, a malaria causing parasite, depends on the parasite’s ability to produce gametocytes, the stage that infects mosquitoes. In many African regions where malaria is common, hemoglobin (Hb) variants such as hemoglobin S (the sickle-cell trait) and C are highly prevalent reflecting their role in protecting against severe disease. However, it remains unclear whether these variants also influence the parasite’s early shift toward gametocyte development (i.e., sexual conversion [SC]). In this study, we combined ex vivo and in vitro SC assays to measure SC in red blood cells with different hemoglobin genotypes. We found that SC was higher in parasites growing in red blood cells carrying hemoglobin AC and AS genotypes compared to normal AA hemoglobin. These findings provide experimental support for earlier epidemiological observations reporting that individuals with these hemoglobin variants often carry more gametocytes and are more infectious to mosquitoes. We also measured antibody levels in individuals with mutant RBCs and found no differences in immunity that could explain the variation in SC. Our results show that host genetic background can influence gametocyte development and may shape the infectious reservoir in high-burden settings. This knowledge is important for designing effective strategies for malaria elimination.
SN  - 1553-7374
ER  -